Over 1 million Americans suffer acute myocardial infarctions each year in the US, and among the survivors, 5 million are afflicted with heart failure. In addition, defects in cell lineage determination or morphogenesis underlie congenital heart malformations, the most common human birth defect. Survivors of congenital heart disease, who number over 1 million in the US, also often suffer from heart failure. Unfortunately, the heart has little regenerative capacity after injury. The recent discovery of human induced pluripotent stem (IPS) cells has opened the door for novel approaches to human disease, including the development of human cellular models for disease mechanisms and drug discovery, along with the potential for autologous cell-based therapies. We propose to assemble a team of investigators at the Gladstone Institutes and Stanford University to develop and capitalize on the potential of IPS cells in the treatment and understanding of heart disease. Methods of IPS generation avoiding genomic integration of DNA are developing rapidly, but continue to require refinement before use of iPS cells in humans; this hurdle will be addressed in this application. As methods for generating IPS cells are improved the team will work together to more efficiently generate iPS-derived cardiac cells for future therapy, capitalizing on their expertise in chromatin remodeling and microRNA (miRNA) biology and G-protein coupled receptor signaling. The team will generate iPS cell lines with fluorescent markers for progressive stages of cardiac differentiation using bacterial artificial chromosome (BAC) strategies. We will also attempt to reprogram somatic cells directly into cardiac progenitors. Survival and engraftment of cells in vivo will be examined in rodents and in large animals through our partners at Stanford. Disease-specific iPS cells will be generated to reveal novel aspects of human progenitor cell biology. This multidisciplinary team will bring broad and critical expertise to the NHLBI Progenitor Cell Consortium in an effort to aggressively capitalize on the promise and potential of iPS cells for heart disease The interaction with the Stanford group within our Hub will synergize and leverage the specific strengths of each group of investigators on the focused effort related to iPS cells. The specific aims are: 1) To develop integration-free and efficient methods of human IPS cell generation for future cell-based therapies; 2) To develop efficient directed differentiation of human IPS cells and methods of direct reprogramming; 3). To develop methods to use IPS cell-derived cardiac progenitors in animal models of cardiovascular disease and 4). To use disease-specific IPS cells for discovery of human cardiac progenitor biology and cardiovascular disease mechanisms.